FGF receptor-4 (FGFR4) polymorphism acts as an activity switch of a membrane type 1 matrix metalloproteinase - FGFR4 complex

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal

36 Scopus Citations
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Author(s)

  • Nami Sugiyama
  • Markku Varjosalo
  • Pipsa Meller
  • Jouko Lohi
  • Zhongjun Zhou
  • Kari Alitalo
  • Jussi Taipale
  • Jorma Keski-Oja
  • Kaisa Lehti

Detail(s)

Original languageEnglish
Pages (from-to)15786-15791
Journal / PublicationProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number36
Publication statusPublished - 7 Sep 2010
Externally publishedYes

Abstract

Tumor cells use membrane type 1 matrix metalloproteinase (MT1-MMP) for invasion and metastasis. However, the signaling mechanisms that underlie MT1-MMP regulation in cancer have remained unclear. Using a systematic gain-of-function kinome screen for MT1-MMP activity, we have here identified kinases that significantly enhance MT1-MMP activity in tumor cells. Inparticular, we discovered an MT1-MMP/FGF receptor-4 (FGFR4) membrane complex that either stimulates or suppresses MT1-MMP and FGFR4 activities, depending on a tumor progression-associated polymorphism in FGFR4. The FGFR4-R388 allele, linked to poor cancer prognosis, increased collagen invasion by decreasing lysosomal MT1-MMP degradation. FGFR4-R388 induced MT1-MMP phosphorylation and endosomal stabilization, and surprisingly, the increased MT1-MMP in return enhanced FGFR4-R388 autophosphorylation. A phosphorylation-defective MT1-MMP was stabilized on the cell surface, where it induced simultaneous FGFR4-R388 internalization and dissociation of cell-cell junctions. In contrast, the alternative FGFR4-G388 variant down-regulated MT1-MMP, and the overexpression of MT1-MMP and particularly its phosphorylation-defective mutant vice versa induced FGFR4-G388 degradation. These results provide a mechanistic basis for FGFR4-R388 function in cancer invasion.

Research Area(s)

  • ECM, Invasion, MMP14, Proteolysis, Signaling

Citation Format(s)

FGF receptor-4 (FGFR4) polymorphism acts as an activity switch of a membrane type 1 matrix metalloproteinase - FGFR4 complex. / Sugiyama, Nami; Varjosalo, Markku; Meller, Pipsa; Lohi, Jouko; Chan, Kui Ming; Zhou, Zhongjun; Alitalo, Kari; Taipale, Jussi; Keski-Oja, Jorma; Lehti, Kaisa.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 36, 07.09.2010, p. 15786-15791.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal